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The co-administration of cannabinol with delta1-tetrahydrocannabinol accelerates the rate of clearance of delta1-tetrahydrocannabinol from rat blood. This increased rate of clearance appears to follow that of cannabinol. The implications of these findings are discussed.
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Rats were trained to respond according to a low rate differential reinforcement (DRL) 72 sec schedule of operant behaviour. The animals were then tested with delta 1-tetrahydrocannabinol (delta 1-THC), cannabinol, and cannabidiol alone and in combination. Tests with single doses of delta 1-THC (dose-range: 0.3-5.6 mg/kg) and cannabinol (dose-range: 1-56 mg/kg) but not cannabidiol (dose-range 3-100 mg/kg), yielded a dose-related biphasic effect on the response rate. Small doses of delta 1-THC and cannabinol increased the rate of responding, large doses of these agents decreased it. Cannabidiol alone only decreased the rate of responding (occurring at large doses). The rate of reinforcement generally was decreased when response rates increased and vice versa. Cannabidiol (10 and 30 kg/kg), together with delta 1-THC (1 and 3 mg/kg), decreased the response output and increased the rate of reinforcement. Similar results were observed with combinations of cannabinol (10 and 30 mg/kg) and cannabidiol (10 and 30 mg/kg). Combinations of delta 1-THC (0.3 and 1 mg/kg) and cannabinol (1 and 3 mg/kg) also reduced the response rate and there were no significant changes in the rate of reinforcement. Hence the actions of delta 1-THC and cannabinol on behaviour in rats maintained by low rate differential reinforcement were similar (approximate difference in potency 1:10), whereas no stimulation of response rate was demonstrated with cannabidiol. Vehicle and day of testing (Tuesday or Friday) variables were found not to affect the results.
The present experiments examined the cannabimimetic potential of cannabinol on its own as well as its interaction with delta 9-tetrahydrocannabinol (delta 9-THC) in vivo. Thus, cannabinol, as evaluated by repeated test procedures using drug-discrimination methodology (Hiltunen and Järbe, 1986; Järbe, Swedberg and Mechoulam, 1981) was found to substitute for the stimulus effects induced by delta 9-THC in both rats (delta 9-THC cue = 3 mg/kg) and pigeons (delta 9-THC cue = 0.56 mg/kg), though, relatively larger doses were required in the latter species (ED50 for cannabinol being 8.4 mg/kg, and 14.1 mg/kg at the time of maximum effect in rats and pigeons, respectively). When administered together, cannabinol added to the cue effects of delta 9-THC as shown by an increase in the percentage of responding appropriate to the drug, the effect appearing more pronounced in rats than in pigeons; no apparent change in the duration of the effect was indicated by the results obtained. Unconditioned effects of drug, as defined by rectal temperature recordings and open-field activity (ambulation, rearing, latency, circling, grooming, defecation and urination), as well as assessment of vocalization in rats were in keeping with the suggestion that the pharmacological profile of cannabinol is similar, though not necessarily identical, to that of tetrahydrocannabinols, such as delta 9-THC.
The in vivo liver metabolism of cannabinol has been studied in the mouse and rat by combined gas chromatography and mass spectrometry. Cannabinol glucuronide was the major metabolite of cannabinol in the mouse and was accompanied by relatively large amounts of 7-hydroxycannabinol, cannabinol-7-oic acid and their corresponding glucuronide conjugates. Lower concentrations of glucuronides were found in the rat. Two series of disubstituted metabolites were found containing either a 7-hydroxyl or a 7-carboxylic acid group and a second hydroxyl group in the 1 inch-4 inch positions of the sidechain. These were of low concentration in the mouse but higher in the rat; 1 inch-hydroxy metabolites were particularly abundant in the latter species. Also found in the rat livers were small amounts of sidechain monohydroxy metabolites and larger quantities of 4 inches, 5 inches-bisnorcannabinol-3 inches-oic acid; these were absent in the mouse. The metabolites were identified using the trimethylsilyl (TMS), [2H9] TMS and methyl ester-TMS derivatives, and by reduction of acid metabolites with lithium aluminium deuteride to the corresponding alcohols.
Elfazepam (7-chloro-1-[2-(ethylsulfonyl)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4benzodiazepin-2-one) and-9-aza-cannabinol )10 hydroxy-beta-(3-methyl-2-octyl)-5',5-dimethyl-5H-1 benzopyranol 3,4-d pyridine, HC1) were administered IV to study their effects on feed intake and acid secretion in abomasal Pavlov pouches in sheep. Elfazepam and 9-aza-cannabinol increased 3-fold 3 hr postinjection feed intake and decreased abomasal acid secretion compared to saline and DMSO (dimethyl sulfoxide) control treatments. At doses which elicit feeding, 9-aza-cannabinol was a much more potent inhibitor of acid secretion than elfazepam. These results are consistent with the theory of localized hypothalamic nuclei which have roles in the control of both feed intake and gastric acid secretion. However, in contrast to feeding associated with normal hunger, the benzodiazepine and cannabinol stimulated feeding is associated with decreased gastric acid secretion.
The effects of the cannabinoids delta 9-tetrahydrocannabinol (THC), cannabinol and cannabidiol on the primary humoral immune response, the secondary humoral immune response and the memory aspect of humoral immunity in response to sheep red blood cell (SRBC) immunization was investigated. Mice treated with THC (10 and 15 mg/kg) during the primary immunization period exhibited a suppression of the primary humoral immune response. Mice treated with THC during the secondary immunization period showed no measurable suppression of the secondary humoral immune response to the immunizing antigen. The memory aspect of humoral immunity was assessed when treatment with cannabinoids was carried out during the primary immunization period and the ability of mice to undergo a secondary immune response was evaluated; suppression of the secondary humoral immune response was evident with THC treatment (10 and 15 mg/kg). Cannabinol and cannabidiol (10 and 25 mg/kg) treated mice showed no impairment in the ability to undergo primary or secondary immune responses with any treatment protocol. In vivo investigations of the effects of cannabinoids on the thymus were also carried out. Thymus weight and thymus cell number were depressed in mice undergoing a primary humoral immune response when treated with THC (10 and 15 mg/kg) during this period. THC treatment, however, did not alter these parameters in mice not challenged with antigen. In both challenged and unchallenged animals, cannabinol and cannabidiol did not measurably alter the thymus.
The ability of cannabinol and delta-8-tetrahydrocannabinol (delta-8-THC), two cannabinoid marihuana components, to modify delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) was investigated in mice. Reduction of DTH reactivity by cannabinol required multiple, daily, postimmunization drug administration. Neither multiple preimmunization dosings nor a single postimmunization dosing was effective. Delta-8-THC produced moderate (13-33%) suppression of DTH reactivity only upon multiple, preimmunization treatments, whereas postimmunization administration only delayed peak DTH reactivity 24 hours without altering the absolute response level. These results indicate that delta-8-THC and cannabinol possess slight to moderate activity in the suppression of DTH.
The butyl homologues of delta1-tetrahydrocannabinol, delta1-tetrahydrocannabinolic acid, cannabinol and cannabidiol have been identified in several samples of cannabis. 8 samples contained delta1-tetrahydrocannabinolic acid, one sample contained cannabinol and one sample contained both cannabinol and cannabidiol. Separation by gas chromatography and identification by gas chromotography-mass spectrometry was achieved by the preparation of trimethylsilyl, d9-trimethylsilyl, triethylsilyl and tri-n-propylsilyl derivatives.
Stable cyclic methyl- and n-butylboronates were prepared from the cannabinolic acids and used as derivatives for the characterization of these compounds by combined gas chromatography mass spectrometry. Retention times of the methylboronates were comparable with those of the trimethylsilyl derivatives. The mass spectra of these derivatives were more characteristic of the cannabinoid skeleton than were the spectra of the trimethylsilyl derivatives where fragmentation was associated with the trimethylsilyl groups. Molecular weights were lower and abundant molecular ions were obtained. These derivatives also offered the possibility of distinguishing between isomeric cannabinolic acids where only isomers possessing adjacent phenolic and carboxylic functions form cyclic boronates.
Six acidic metabolites were isolated from rat faeces and identified by gas chromatographymass spectrometry and proton magnetic resonance. Cannabinol-7-oic acid was the most abundant acidic metabolite isolated. Others present in decreasing order of prominence were 1"-hydroxy-, 4"-hydroxy-, 3"-hydroxycannabinol-7-oic acid, cannabinol-3"-one-7-oic acid and 2"-hydroxycannabinol-7-oic acid.
Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose-related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5-mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5-mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7-day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.
Fifty-five clinical trials were conducted to determine the cardiovascular combined effects of stressful oral surgery and systemic cannabinols. In a first study, delta9-tetrahydrocannabinol (THC) was given IV as a premedicant and compared with diazepam and with a placebo. A classic dose-related tachycardia followed THC injection. The peak heart rate response of patients premedicated with 0.044 mg/kg THC was 24.1% higher (p less than 0.05) than the peak effect for a nonsurgerized control group, suggesting a synergistic effect between THC and surgical stress. A predisposition to syncopal hypotension followed THC premedication, and antiarrhythmic effects were observed after large doses. The injection of local anesthetic preparations containing epinephrine did not alter THC cardiovascular response. An apparent drug interaction was observed, however, in a second study, in patients given general anesthesia within 72 hours after smoking marijuana. These patients demonstrated sustained abnormal postoperative tachycardia when compared with control nonsmokers, an effect which may have resulted from an interaction between stored cannabinol metabolites and atropine administered as part of the anesthetic technic. It was concluded that THC had no particular advantage over diazepam or placebo as a premedicant. Further, THC altered the patients' adaptivity to stress and interacted undesirably with other anesthetic medications.
An antiserum raised in sheep against a conjugate of tetrahydrocannabinol with bovine serum albumin has been used as the basis of a radioimmunoassay for cannabinoids in the blood of rabbits given tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, cannabinol or cannabidiol by rapid intravenous injection. In the case of both 11-hydroxy-tetrahydrocannabinol and cannabinol plasma cannabinoid concentrations fell exponentially from an initial peak plasma level attained immediately after the completion of intravascular distribution of the injected bolus. In the case of tetrahydrocannabinol itself, however, there was a progressive rise in plasma cannabinoid concentration between five and fifteen minutes after the rapid intravenous injection. The reasons for this rise in plasma cannabinoid concentration are discussed.
Partially purified glucuronyltransferase immobilized on beaded sepharose has been used to synthesize the glucuronide conjugates of cannabinol, cannabidol, delta9-tetrahydrocannabinol and delta8-tetrahydrocannabinol. Trimethylsilylated methyl esters and per(trimethylsilyl) derivatives of these conjugates have been characterized by their gas chromatographic retention times and their electron impact and ammonia chemical ionization mass spectra.
The single dose pharmacokinetics of deuterium-labelled cannabinol (2H2-CBN) were evaluated in six male cannabis users with different degree of abuse after smoking an average dose of 19 mg and after intravenous administration of 20 mg CBN. Plasma levels were measured for up to 72 h with selected ion monitoring by GC/MS using 2H7-CBN as internal standard. The systemic availability of smoked CBN was found to be 39 +/- 26% (min-max 6-65%). The mean plasma clearance was 19.1 +/- 2.6 ml min-1 kg-1 and the volume of distribution was determined to 50 +/- 23 l kg-1. The apparent terminal half lives for CBN were 32 +/- 17 h and 43 +/- 29 h after intravenous administration and smoking, respectively.
Metabolism of cannabinol (CBN) was studied in hepatic microsomal incubates from mouse, rat, rabbit, guinea pig, cat, hamster and gerbil. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and identified by GC/MS as TMS derivatives. Six monohydroxy metabolites were identified. These had hydroxy groups at C-11 and at all positions of the pentyl side-chain. Metabolism varied considerably between the species. 11-Hydroxylation was the most prominent route in the majority of species, but in the hamster and cat the major metabolic pathway was 4'-hydroxylation. Metabolites hydroxylated in the pentyl chain were generally more abundant in guinea pig, hamster and cat.